Ophthalmic compositions containing a synergistic combination of three polymers

ABSTRACT

Ophthalmic compositions suitable for use as artificial tears or as vehicles for ophthalmic drugs are disclosed. The compositions contain a combination of three polymers that have a synergistic effect on viscosity.

This application is a continuation-in-part of U.S. Ser. No. 10/863,172,filed Jun. 8, 2004, which claims priority to U.S. ProvisionalApplication, U.S. Ser. No. 60/478,713, filed Jun. 13, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pharmaceutical compositions. Inparticular, this invention relates to topically administrable ophthalmiccompositions that contain three polymeric components.

2. Description of Related Art

The use of polymeric ingredients in topically administrable ophthalmiccompositions is well known. Polymeric ingredients are typically used insuspension compositions as physical stability aids, helping to keep theinsoluble ingredients suspended or easily redispersible. In solutioncompositions, polymeric ingredients are typically used to increase thecomposition's viscosity.

Many polymers have been used in topically administrable ophthalmiccompositions. Included among these are cellulosic polymers, such ashydroxypropyl methylcellulose, hydroxyethyl cellulose, andethylhydroxyethyl cellulose. Also included are synthetic polymers, suchas carboxyvinyl polymers and polyvinyl alcohol. Still others includepolysaccharides such as xanthan gum, guar gum, and dextran.

Combinations of polymers have also been used in ophthalmic compositions.Certain combinations of polymers are known to provide synergisticeffects on viscosity and, in some cases, even a phase transition from aliquid to a gel. For example, U.S. Pat. No. 4,136,173 disclosesophthalmic compositions containing a combination of xanthan gum andlocust bean gum.

One approach to achieving a target viscosity in a topicallyadministrable ophthalmic composition might involve simply adding asufficient amount of one polymeric ingredient. Often, however, it isdesirable to minimize the total amount of polymeric additives intopically administrable ophthalmic compositions. A mixed polymer systemcontaining more than one polymer can significantly enhance the viscosityand lubrication property of a composition while minimizing total polymerconcentration and cost of materials.

SUMMARY OF THE INVENTION

The present invention is directed toward ophthalmic compositions thatcontain three polymeric components. The compositions containhydroxypropyl methylcellulose and a combination of two polymers selectedfrom the group of combinations consisting of guar gum and a carboxyvinylpolymer; guar gum and hydroxyethyl cellulose; guar gum and dextran;hydroxyethyl cellulose and a carboxyvinyl polymer; and dextran and acarboxyvinyl polymer. The compositions are useful as artificial tearproducts, but can also serve as vehicles for delivering ophthalmicdrugs.

The present invention is based upon the finding that the specifiedcombinations of three polymers have a synergistic effect on viscosity.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the viscosity for each of Compositions 1-8 (Example 2),demonstrating the remarkable synergy among the three polymer system:hydroxypropyl methylcellulose, guar gum and carboxyvinyl polymer.

FIG. 2 shows the effect of total polymer concentration on viscosity forthe three polymer system of hydroxypropyl methylcellulose, guar gum andcarboxyvinyl polymer for a concentration ratio of 3:1:1 (hydroxypropylmethylcellulose:guar gum:carboxyvinyl polymer) at pH 7.0.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, all ingredient concentrations are listed asa weight/volume percentage basis (% w/v).

The ophthalmic compositions of the present invention are aqueouscompositions that include a combination of three polymeric ingredients:hydroxypropyl methylcellulose (“HPMC”) and a combination of two polymersselected from the group of combinations consisting of guar gum (“Guar”)and a carboxyvinyl polymer (“carbomer”); Guar and hydroxyethyl cellulose(“HEC”); Guar and dextran; HEC and carbomer; and dextran and carbomer.All of these types of polymers are known and have been used inophthalmic compositions. All of these types of polymers are alsocommercially available.

HPMC is commercially available from the Dow Chemical Company under thebrand name Methocel®. HPMC is available in a variety of grades. Mostpreferred for use in the compositions of the present invention isMethocel E4M, (HPMC 2910), which has a number average molecular weightof approximately 86,000 dalton. The concentration of HPMC in thecompositions of the present invention will generally range from0.05-0.5%, and will preferably be 0.3%.

Guar includes guar gum and guar gum derivatives, such as thehydroxypropyl or hydroxypropyltrimonium chloride derivatives of guargum. Guar and its derivatives are described in U.S. Pat. No. 6,316,506,the entire contents of which are hereby incorporated by reference. Forpurposes of the present application, guar includes unsubstituted guargum and its substituted derivatives. Guar gum and many of itsderivatives are commercially available from Rhone-Poulenc (Cranbury,N.J.), Hercules, Inc. (Wilmington, Del.) and TIC Gum, Inc. (Belcamp,Md.). A preferred derivative for use in the compositions of the presentinvention is hydroxypropyl guar (“HP-Guar”). The concentration of guarin the compositions of the present invention will generally range from0.01-0.2%, and will preferably be 0.1%.

Carboxyvinyl polymers suitable for use in the present invention are alsoknown as “carbomers” or carboxypolymethylene. They are commerciallyavailable from sources such as Noveon, Inc. (Cleveland, Ohio), whichdistributes them under the trade name Carbopol®. Carbopol polymers arecrosslinked, acrylic acid-based polymers. They are cross-linked withallyl sucrose or allylpentaerythritol. Carbopol copolymers are polymersof acrylic acid, modified by C₁₀₋₃₀ alkyl acrylates, and crosslinkedwith allylpentaerythritol. A preferred carbomer for use in thecompositions of the present invention is a polymer of acrylic acidcross-linked with allyl sucrose or allylpentaerythritol, which iscommercially available as Carbopol® 974P. The concentration of carbomerin the compositions of the present invention will generally range from0.01-0.2%, and will preferably be 0.1%.

HEC is commercially available from Hercules Inc. (Aqualon Division) in avariety of grades, including Natrasol 250 LR, Natrasol 250 MR andNatrasol 250 HR. A preferred HEC for use in the compositions of thepresent invention is the NF grade material, which is commerciallyavailable as Natrasol 250HR. The concentration of HEC in thecompositions of the present invention will generally range from0.05-0.5%, and will preferably range from 0.1-0.2%.

Dextran is commercially available from Amresco in a variety of grades,including Dextran 5, 10, 20, 40, 70, 110, 500, and 2000. A preferreddextran for use in the compositions of the present invention is Dextran70 (NOC grade; dry powder). The concentration of dextran in thecompositions of the present invention will generally range from0.01-0.2%, and will preferably be 0.1%.

The aqueous compositions of the present invention contain the threespecified polymeric ingredients in a ratio ranging from 1:1:1 to 3:3:3,with a ratio of 3:1:1 being most preferred, where the amount of HPMC islisted first and the amounts of the other two polymers are listed secondand third, respectively. The total concentration of the three polymericingredients should range from 0.1-1%, preferably 0.3-0.9%, and mostpreferably, 0.4-0.7%.

In addition to the three required polymeric ingredients, the aqueouscompositions of the present invention may contain other ingredients asexcipients. For example, the compositions may include one or morepharmaceutically acceptable buffering agents, preservatives (includingpreservative adjuncts), tonicity-adjusting agents, surfactants,solubilizing agents, stabilizing agents, comfort-enhancing agents,emollients, pH-adjusting agents and/or lubricants. Preferably, theaqueous composition does not contain any polymeric ingredients, otherthan the synergistic combination of the three polymeric ingredientsspecified above, with the exception of polymeric preservatives forcompositions that contain a preservative. If the compositions contain acarbomer as one of the three polymers, then the compositions of thepresent invention do not contain any ionic tonicity-adjusting agents,such as sodium chloride, or other ionic excipients, such as boric acid,as these ingredients have a significant, detrimental effect on thecomposition's viscosity.

The compositions of the invention have a pH in the range of 4-9,preferably 6-8, and most preferably 6.5-7.5. If the compositions containa carbomer as one of the three polymers, it is critical that thecompositions are formulated so that the target pH is not exceeded. Oncea target pH has been exceeded in compositions containing a carbomer,adding an acid such as hydrochloric acid to adjust the pH downward cancompromise the synergistic viscosity. Even relatively small amounts ofacid or salts, on the order of 0.005%, can have a significant effect onthe viscosity of compositions containing a carbomer.

The compositions of the present invention generally have an osmolalityin the range of 220-340 mOsm/kg, and preferably have an osmolality inthe range of 235-300 mOsm/kg.

The aqueous compositions of the present invention are suitable for useas artificial tear products to relieve symptoms of dry eye.Alternatively, the compositions of the present invention may act as avehicle for an ophthalmic drug. Ophthalmic drugs suitable for use in thecompositions of the present invention include, but are not limited to:anti-glaucoma agents, such as beta-blockers including timolol,betaxolol, levobetaxolol, carteolol, miotics including pilocarpine,carbonic anhydrase inhibitors, prostaglandins, seretonergics,muscarinics, dopaminergic agonists, adrenergic agonists includingapraclonidine and brimonidine; anti-angiogenesis agents; anti-infectiveagents including quinolones such as ciprofloxacin, and aminoglycosidessuch as tobramycin and gentamicin; non-steroidal and steroidalanti-inflammatory agents, such as suprofen, diclofenac, ketorolac,rimexolone and tetrahydrocortisol; growth factors, such as EGF;immunosuppressant agents; and anti-allergic agents includingolopatadine. The ophthalmic drug may be present in the form of apharmaceutically acceptable salt, such as timolol maleate, brimonidinetartrate or sodium diclofenac. Compositions of the present invention mayalso include combinations of ophthalmic drugs, such as combinations of(i) a beta-blocker selected from the group consisting of betaxolol andtimolol, and (ii) a prostaglandin selected from the group consisting oflatanoprost; 15-keto latanoprost; travoprost; and unoprostone isopropyl.In the case of a cationic drug, the amount of drug and/or the amount ofcarboxyvinyl polymer and/or the identity and amount of other formulationingredients may need to be adjusted to minimize or eliminateinteractions between the carboxyvinyl polymer and the cationic drug.Preferably, the ophthalmic drug is a neutral or negatively-charged drug.

Although the amount of drug included in the compositions of the presentinvention will be whatever amount is therapeutically effective and willdepend upon a number of factors, including the identity and potency ofthe chosen drug, the total concentration of drug will generally be about5% or less.

The compositions of the present invention are preferably not formulatedas solutions that undergo a phase transition to a gel uponadministration to the eye. The compositions illustrated in the Examplesbelow do not gel upon administration to the eye.

The compositions of the present invention may be topically applied tothe eye or injected into the eye, depending upon the target site anddisease or condition to be treated. To treat diseases or conditionsinside the eye rather than at the surface of the eye, the compositionsof the present invention may, for example, be administered byintravitreal injection, subconjunctival injection, sub-tenon injection,retrobulbar injection, suprachoroidal injection, or periocularinjection. A syringe apparatus including an appropriately sized needle,for example, a 27 gauge needle or a 30 gauge needle, can be effectivelyused to inject the composition into the posterior segment of an eye of ahuman or animal. The combination of polymers may be particularlyadvantageous for injections into the eye for the following reasons:prevention of reflux, prolonged duration of action so as to increase theperiod of time between repeat injections, and reduction in the totalamount of polymer required to achieve a target viscosity, therebyreducing the polymer disposition from back of the eye.

The following examples are presented to illustrate further variousaspects of the present invention, but are not intended to limit thescope of the invention in any respect.

EXAMPLES Example 1 Artificial Tear Composition

A representative formulation for an artificial tear product according tothe present invention is shown in Table 1.

TABLE 1 Ingredients Concentration (% w/w) HPMC 2910 0.3 HP-Guar 0.1Carbopol 974P 0.1 Mannitol 4.0 NaOH/HCl qs to pH 7.0 Purified water qsto 100

The composition shown in Table 1 can be prepared by at least twomethods. One method involves adding the following ingredients slowly andin the following order to heated purified water (70-80° C.)(approximately 80% of the desired batch volume) with mixing: mannitol,HPMC 2910, Carbopol 974P, and HP-Guar (waiting until each ingredient ismixed well before adding the next). pH is then adjusted with 1N NaOH,and the remaining amount of purified water is added. The composition isthen autoclaved at 121° C. for thirty minutes and subsequently cooled toroom temperature with constant stirring.

An alternative method of preparing the composition shown in Table 1 isas follows. In a first container, add heated purified water (70-80° C.)(approximately 60% of the desired batch volume), then mix in mannitol,then HPMC 2910, and then Carbopol 974P, waiting until each ingredient ismixed well before adding the next. Autoclave the resulting compositionat 121° C. for thirty minutes, then allow the composition to cool toroom temperature with constant stirring (“the HPMC/Carbopolcomposition”). In a separate container, add purified water(approximately 30% of the desired batch volume), then mix in HP-Guar.Adjust the pH of the HP-Guar composition with 1N NaOH to pH 9. Autoclavethe HP-Guar composition at 121° C. for thirty minutes, then allow it tocool to room temperature with constant stirring (“the HP-Guarcomposition”), then aseptically combine the HP-Guar composition with theHPMC/Carbopol composition, and aseptically adjust the final pH to 7.0,if necessary, with 1N NaOH and/or 1N HCl.

Example 2 Synergistic Effect on Viscosity (HPMC+Guar+Carbomer)

The compositions shown in Table 2 were prepared and their viscositydetermined using a Brookfield cone/plate viscometer with number 42cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosityless than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) formore viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 2 and in FIG. 1.

TABLE 2 Composition (% w/v) Ingredient 1 2 3 4 5 6 7 8 Mannitol 4.0 4.04.0 4.0 4.0 4.0 4.0 4.0 HPMC — 0.3 — — 0.3 0.3 — 0.3 2910 Carbopol — —0.1 — 0.1 — 0.1 0.1 974P HP-Guar — — — 0.1 — 0.1 0.1 0.1 NaOH/HCl q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pH pH pH pH pH 7.0 7.0 7.07.0 7.0 7.0 7.0 7.0 Purified q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.Water 100 100 100 100 100 100 100 100 Viscosity 1.1 8.2 488.1  5.31339.5   32.3  1273.0   2477.0   (cps) Subst. — — — — — — — YesSynergy^(@) ^(@)Subst. Synergy = substantial synergy: greater than 150%of the simple sum of the three respective single polymer solutions

Example 3 Synergistic Effect on Viscosity (HPMC+HEC+Guar;HPMC+HEC+Carbomer)

The compositions shown in Table 3 were prepared and their viscositydetermined using a Brookfield cone/plate viscometer with number 42cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosityless than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) formore viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 3.

TABLE 3 Composition (% w/v) Ingredient 9 10 11 12 13 14 15 16 17 18Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 HPMC — 0.3 — — — 0.3 —— 0.3 0.3 2910 HP-Guar — — 0.1 — — — 0.1 — 0.1 — Carbopol — — — 0.1 — —— 0.1 — 0.1 974P Natrasol — — — — 0.1 0.1 0.1 0.1 0.1 0.1 250HR NaOH/HClq.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pH pH pH pHpH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. Water 100 100 100 100 100 100 100 100100 100 Viscosity 1.0 8.0 5.2 465.9  3.0 27.7  10.9  642.0  62.8 1300.5   (cps) Subst. — — — — — — — — Yes Yes Synergy^(@) ^(@)Subst.Synergy = substantial synergy: greater than 150% of the simple sum ofthe three respective single polymer solutions

Example 4 Lack of Synergistic Effect on Viscosity (PolyvinylAlcohol+Chondroitin Sulfate+Polyvinylpyrrolidone)

The compositions shown in Table 4 were prepared and their viscositydetermined using a Brookfield cone/plate viscometer with number 42cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosityless than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) formore viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 4. Airvol 523S is a commercially availablepolyvinyl alcohol polymer. Chondroitin sulfate is a commerciallyavailable polymer. K90 is a commercially available polyvinylpyrrolidonepolymer.

TABLE 4 Composition (% w/v) Ingredient 19 20 21 22 23 24 25 26 Mannitol4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 PVA (Airvol — 0.2 — — 0.2 0.2 — 0.2523S) Chondroitin — — 0.2 — 0.2 — 0.2 0.2 Sulfate PVP (K90) — — — 0.2 —0.2 0.2 0.2 NaOH/HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pHpH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified Water q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. 100 100 100 100 100 100 100 100 Viscosity(cps) 1.0 1.5 1.3 1.4 1.7 1.9 1.8  2.3* Subst. — — — — — — — NoSynergy^(@) *slight, transparent precipitate observed ^(@)Subst. Synergy= substantial synergy: greater than 150% of the simple sum of the threerespective single polymer solutions

Example 5 Lack of Synergistic Effect on Viscosity (PolyvinylAlcohol+Chondroitin Sulfate+Carbomer; PolyvinylAlcohol+Polyvinylpyrrolidone+Carbomer; ChondroitinSulfate+Polyvinylpyrrolidone+Carbomer)

The compositions shown in Table 5 were prepared and their viscositydetermined using a Brookfield cone/plate viscometer with number 42cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosityless than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) formore viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 5. Airvol 523S is a commercially availablepolyvinyl alcohol polymer. Chondroitin sulfate is a commerciallyavailable polymer. K90 is a commercially available polyvinylpyrrolidonepolymer. The viscosities of the single polymer solutions for polyvinylalcohol, chondroitin sulfate and polyvinylpyrrolidone can be found inTable 4—Examples 20-22.

TABLE 5 Composition (% w/v) Ingredient 27 28 29 30 31 32 33 Mannitol 4.04.0 4.0 4.0 4.0 4.0 4.0 PVA — 0.2 — — — 0.2 0.2 (Airvol 523S)Chondroitin — — 0.2 — 0.2 0.2 — Sulfate PVP — — — 0.2 0.2 — 0.2 (K90)Carbopol 974P 0.1 0.1 0.1 0.1 0.1 0.1 0.1 NaOH/HCl q.s. q.s. q.s. q.s.q.s. q.s. q.s. pH pH pH pH pH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 PurifiedWater q.s. q.s. q.s. q.s. q.s. q.s. q.s. 100 100 100 100 100 100 100Viscosity (cps) 441.6  323.8  12.7  N/A*  16.7** 14.2  N/A* Subst. — — —— — No No Synergy^(@) *PVP was incompatible with Carbopol 974P - itformed a precipitate. **Solution obtained only by specific order ofmixing: mannitol, then chondroitin sulfate, then PVP, then carbomer.^(@)Subst. Synergy = substantial synergy: greater than 150% of thesimple sum of the three respective single polymer solutions

Example 6 Synergistic Effect on Viscosity (HPMC+HEC+Guar;HPMC+HEC+Carbomer)

The compositions shown in Table 6 were prepared and their viscositydetermined using a Brookfield cone/plate viscometer with number 42cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosityless than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) formore viscous samples (viscosity more than 20 cps). Two peopleindependently prepared the indicated samples and measured theirviscosity values (n=1) for each person. The averages of each set ofresults are shown in Table 6.

TABLE 6 Composition (% w/v) Ingredient 34 35 36 37 38 39 40 41 42 43Mannitol 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 HPMC — 0.3 — — — 0.3 —— 0.3 0.3 2910 HP-Guar — — 0.1 — — — 0.1 — 0.1 — Carbopol — — — 0.1 — —— 0.1 — 0.1 974P Dextran — — — — 0.1 0.1 0.1 0.1 0.1 0.1 70 NaOH/HClq.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. pH pH pH pH pH pH pHpH pH pH 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 7.0 Purified q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. Water 100 100 100 100 100 100 100 100100 100 Viscosity 1.1 7.9 5.2 461.6  1.4 8.4 5.2 379.3  46.1  829.2 (cps) Subst. — — — — — — — — Yes Yes Synergy^(@) ^(@)Subst. Synergy =substantial synergy: greater than 150% of the simple sum of the threerespective single polymer solutions

Example 7 The Effect of Polymer Ratio on Viscosity

The effect of polymer ratio on viscosity was determined by preparingcompositions containing a ratio of the three designated polymers thatvaried from 1:1:1 to 3:3:3. The compositions are shown in Table 5. Theviscosity was determined using a Bohlin Rheometer Model CS-10 at 25° C.(shear rate: 0.8 1/s). Two people independently prepared the indicatedcompositions and determined viscosity values (n=10 for each person). Theaverages of the results are shown in Table 7.

TABLE 7 Composition (% w/v) Ingredient 44 45 46 47 48 Mannitol 4.0 4.04.0 4.0 4.0 HPMC 2910 0.1 0.1 0.1 0.3 0.3 Carbopol 0.1 0.1 0.3 0.1 0.3974P HP-Guar 0.1 0.3 0.1 0.1 0.3 NaOH/HCl q.s. q.s. q.s. q.s. q.s. pH7.0 pH 7.0 pH 7.0 pH 7.0 pH 7.0 Purified q.s. 100 q.s. 100 q.s. 100 q.s.100 q.s. 100 Water Polymer ratio 1:1:1 1:1:3 1:3:1 3:1:1 3:3:3HPMC:Carbopol:HP- Guar Viscosity 2865 8450 101950 3660 145000 (cps)[700] [1655] [2899] [141] [1414] [Stnd. Deviation]

Example 8 Effect of Salt on Viscosity for a Polymer Combination thatContains Carbomer

The compositions shown below in Table 8 were prepared to determine theeffect of the addition of salt (NaCl) on viscosity. The viscosity ofeach sample was determined using a Brookfield cone/plate viscometer (52cone, 3 rpm). The results are shown in Table 8.

TABLE 8 Composition (% w/v) INGREDIENT Ex. 1 X Y Z AA Mannitol 4.0 4.04.0 4.0 4.0 HPMC 29.0 0.3 0.3 0.3 0.3 0.3 Carbopol 974P 0.1 0.1 0.1 0.10.1 HP Guar 0.1 0.1 0.1 0.1 0.1 NaCl 0 0.001 0.005 0.01 0.05 NaOH/HClq.s. q.s. q.s. q.s. q.s. pH 7.0 pH 7.0 pH 7.0 pH 7.0 pH 7.0 PurifiedWater q.s. 100 q.s. 100 q.s. 100 q.s. 100 q.s. 100 Viscosity (cps) 15691382 774 608 202

Example 9 Effect of Boric Acid on Viscosity for a Polymer Combinationthat Contains Carbomer

The compositions shown below in Table 9 were prepared to determine theeffect of the addition of boric acid on viscosity. The viscosity of eachsample was determined using a Brookfield cone/plate viscometer (52 cone,3 rpm). The results are shown in Table 9.

TABLE 9 Composition (% w/v) INGREDIENT Ex. 1 X Y Z AA Mannitol 4.0 4.04.0 4.0 4.0 HPMC 2910 0.3 0.3 0.3 0.3 0.3 Carbopol 974P 0.1 0.1 0.1 0.10.1 HP Guar 0.1 0.1 0.1 0.1 0.1 Boric acid 0 0.001 0.005 0.01 0.05NaOH/HCl q.s. q.s. pH 7 q.s. pH 7 q.s. pH 7 q.s. pH 7 pH 7 PurifiedWater q.s. 100 q.s. 100 q.s. 100 q.s. 100 q.s. 100 Viscosity (cps) 12501035 682 531 172

Example 10 Effect of Total Polymer Concentration on Viscosity

The effect of total polymer concentration on the viscosity ofcompositions containing a combination of HPMC 2910, HP-Guar and Carbopol974P was evaluated using 5 compositions containing only the threedesignated polymers, mannitol and purified water. In each case, thecomposition contained 4.0% (w/w) of mannitol and had an adjusted pH of7.0. The total polymer concentrations ranged from 0.1 to 1.0, with theratio of polymers held constant at 3:1:1 (HPMC:HP-Guar:Carbopol). Theviscosity was determined using a Bohlin Rheometer Model CS-10 at 25° C.(shear rate: 0.8 1/s). The results (average of 10 measurements, n=10)are shown in Table 10 and FIG. 2.

TABLE 10 Total Polymer Concentration (% w/v) Viscosity (cps) 0.1 48 0.2583 0.5 3087 0.75 21,099 1.0 44,064

The invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspirit or essential characteristics. The embodiments described above aretherefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

1. A method of treating a disease or condition of the eye comprising administering to the eye a composition comprising an ophthalmic drug and a carrier wherein the carrier comprises three polymeric ingredients having a synergistic effect on the composition's viscosity and wherein the three polymeric ingredients are a) guar gum, b) hydroxypropyl methyl cellulose and c) carboxyvinyl polymer, provided that if the composition comprises a carboxyvinyl polymer then the composition does not contain sodium chloride or boric acid wherein the viscosity of the composition is greater than 150% of the sum of the viscosities of three single polymer compositions that contain only one of the three polymer ingredients, respectively.
 2. The method of claim 1 wherein the composition is administered topically to the eye.
 3. The method of claim 1 wherein the composition is injected.
 4. The method of claim 3 wherein the composition is injected as an intravitreal injection, subconjunctival injection, sub-tenon injection, retrobulbar injection, suprachoroidal injection, or periocular injection.
 5. The method of claim 1 wherein the guar gum ingredient is hydroxypropyl guar.
 6. The method of claim 1 wherein the composition includes the carboxyvinyl polymer and the carboxyvinyl polymer is a polymer of acrylic acid crosslinked with allyl sucrose or allylpentaerythritol.
 7. The method of claim 1 wherein the three polymeric ingredients are present in a ratio of 1:1:1 to 3:3:3, and the total concentration of the three polymeric ingredients ranges from 0.1-1% (w/v).
 8. The method of claim 1 wherein the total concentration of the three polymeric ingredients ranges from 0.4-0.7% (w/v).
 9. The method of claim 1 wherein the ophthalmic drug is selected from the group consisting of anti-glaucoma agents; anti-angiogenesis agents; anti-infective agents; non-steroidal and steroidal anti-inflammatory agents; growth factors; immunosuppressant agents; and anti-allergic agents.
 10. The method of claim 1 wherein the composition has a pH of 6-8 and an osmolality in the range of 235-300 mOsm/kg.
 11. A method of treating a disease or condition of the eye comprising administering to the eye a composition comprising an ophthalmic drug and a carrier wherein the carrier comprises three polymeric ingredients having a synergistic effect on the composition's viscosity and wherein the three polymeric ingredients are a) guar gum, b) hydroxypropyl methyl cellulose and c) carboxyvinyl polymer; or wherein the three polymeric ingredients are hydroxypropyl methylcellulose and a combination of two polymers selected from the group of combinations consisting of guar gum and a carboxyvinyl polymer; guar gum and hydroxyethyl cellulose; guar gum and dextran; hydroxyethyl cellulose and a carboxyvinyl polymer; and dextran and a carboxyvinyl polymer wherein the viscosity of the composition is greater than 150% of the sum of the viscosities of three single polymer compositions that contain only one of the three polymer ingredients, respectively.
 12. The method of claim 11 wherein the composition is administered topically to the eye.
 13. The method of claim 11 wherein the composition is injected.
 14. The method of claim 13 wherein the composition is injected as an intravitreal injection, subconjunctival injection, sub-tenon injection, retrobulbar injection, suprachoroidal injection, or periocular injection.
 15. The method of claim 11 wherein the guar gum ingredient is hydroxypropyl guar.
 16. The method of claim 11 wherein the carboxyvinyl polymer is a polymer of acrylic acid crosslinked with allyl sucrose or allylpentaerythritol.
 17. The method of claim 11 wherein the three polymeric ingredients are present in a ratio of 1:1:1 to 3:3:3, and the total concentration of the three polymeric ingredients ranges from 0.1-1% (w/v).
 18. The method of claim 11 wherein the total concentration of the three polymeric ingredients ranges from 0.4-0.7% (w/v).
 19. The method of claim 11 wherein the ophthalmic drug is selected from the group consisting of anti-glaucoma agents; anti-angiogenesis agents; anti-infective agents; non-steroidal and steroidal anti-inflammatory agents; growth factors; immunosuppressant agents; and anti-allergic agents.
 20. The method of claim 11 wherein the composition has a pH of 6-8 and an osmolality in the range of 235-300 mOsm/kg. 